Field of the Invention
[0001] The present invention relates generally to the methods for the treatment of conditions
mediated by IL-5 and excess eosinophil production and methods of administering compounds
for the treatment of these conditions.
Background of the Invention
[0002] Eosinophils have been implicated in the pathogenesis of a wide variety of inflammatory
disease states including allergic disorders associated with hypersensitivity reactions
in the lung tissue (
Butterfield et al., In: Immunopharmacology of Eosinophils, H. Smith and R. Cook, Eds.,
p.151-192, Academic Press, London (1993)). A notable example is asthma, a disease characterized by reversible obstruction
of the airways leading to non-specific bronchial hyperresponsiveness. This obstruction
in turn is dependent upon the generation of a chronic inflammatory reaction at the
level of the bronchial mucosa and a characteristic infiltration by macrophages, lymphocytes
and eosinophils. The eosinophil appears to play a central role in initiating the mucosal
damage typical of the disease (
Corrigan et al., Immunol. Today, 13:501-507 (1992)). Increased numbers of activated eosinophils have been reported in the circulation,
bronchial secretions and lung parenchyma of patients with chronic asthma, and the
severity of the disease, as measured by a variety of lung function tests, correlates
with blood eosinophil numbers (
Griffen et al., J. Aller. Clin. Immunol., 67:548-557 (1991)). Increased numbers of eosinophils, often in the process of degranulation, have
also been recovered in bronchoalveolar lavage (BAL) fluids of patients undergoing
late asthmatic reactions, and reducing eosinophil numbers, usually as a consequence
of steroid therapy, is associated with improvements in clinical symptoms (
Bousquet et al., N. Eng. J. Med., 323:1033-1039 (1990)).
[0003] Interleukin 5 (IL-5) is a homodimeric glycoprotein produced predominantly by activated
CD4+ T lymphocytes. In man, IL-5 is largely responsible for controlling the growth
and differentiation of eosinophils. Elevated levels of IL-5 are detected in the bronchoalveolar
lavage washings of asthmatics (
Motojima et al., Allergy, 48:98 (1993)). Mice which are transgenic for IL-5 show a marked eosinophilia in peripheral blood
and tissues in the absence of antigenic stimulation (
Dent et al., J. Exp. Med., 172:1425 (1990)) and anti-murine IL-5 monoclonal antibodies have been shown to have an effect in
reducing eosinophilia in the blood and tissues of mice (
Hitoshi et al., Int. Immunol., 3:135 (1991)) as well as the eosinophilia associated with parasite infection and allergen challenge
in experimental animals (
Coffman et al., Science, 245:308-310 (1989),
Sher et al., Proc. Natl. Acad. Sci., 83:61-65 (1990),
Chand et al., Eur. J. Pharmacol., 211:121-123 (1992)).
[0004] Although corticosteroids are extremely effective in suppressing eosinophil numbers
and other inflammatory components of asthma, there are concerns about their side effects
in both severe asthmatics and more recently in mild to moderate asthmatics. The only
other major anti-inflammatory drug therapies - cromoglycates (cromolyn sodium and
nedocromil) - are considerably less effective than corticosteroids and their precise
mechanism of action remains unknown.
[0005] The primary beneficial function of eosinophils is considered to be host protection
against parasitic helminth infections (
Klion AD, Nutman TB. J Allergy Clin Immunol 2004; 113: 30-7) and possibly some viruses (
Rothenberg ME, Hogan SP. Annu Rev Immunol 2006; 24: 147-74). Parasitic invasion prompts rapid recruitment of eosinophils from the circulation
to the site of infection, where they initiate and advance the immune response through
a variety of mechanisms, including antigen presentation, and the secretion of proinflammatory
cytokines, chemokines, lipid mediators and cytotoxic granule proteins (
Kariyawasam HH, Robinson DS. Semin Respir Crit Care Med 2006; 27: 117-27 and Klion, et al.). Allograft and tumour antigens may also activate eosinophils and
trigger degranulation, suggesting a potential role for eosinophils in organ transplant
rejection and defence against malignant tumours (
Munitz A, Levi-Schaffer F. Allergy 2004; 59: 268-75).
[0006] Eosinophils have been implicated in a number of disease pathologies. Inappropriate
secretion of cytokines and other effector molecules from eosinophils causes damage
and dysfunction to the surrounding tissue. End-organ damage resulting from eosinophil
infiltration and activation represents a common pathogenic component of several disease
states, including atopic diseases and hypereosinophilic syndromes (HES). Thus, there
is a need for the methods of the present invention to reduce eosinophils in a human
in need thereof.
Summary of the invention
[0007] In one embodiment of the present invention, methods are provided for reducing eosinophils
in a human in need thereof, which method comprises administering to said human a composition
comprising at least one anti-IL-5 antibody, wherein said anti-IL-5 antibody provides
a mean maximum plasma concentration of said anti-IL-5 antibody of at least about 1.03
± 0.21 µg/mL and an Area Under the Curve value of said anti-IL-5 antibody is at least
about 15.5 ± 2.7 µg/day/mL.
[0008] In another embodiment methods are provided for treating nasal polyposis, in a human,
comprising the step of administering to said human in need thereof an effective amount
of a composition comprising at least one anti-IL-5 antibody wherein said antibody
comprises a heavy chain and a light chain.
Detailed Description of the Invention
I. Definitions.
[0009] As used herein an "anti-IL-5 antibody" refers to any antibody, antibody fragment
or single chain antibody that binds to the cytokine IL-5 from any species. An anti-IL-5
antibody may be murine, chimeric, humanized or fully human. The antibody may be neutralizing.
Several examples of anti-IL-5 antibodies are described in
U.S. Patent Nos. 5,683,892,
5,693,323,
5,783,184,
5,851,525,
6,129,913,
5,096,071,
6,056,957, and
6,451,982, herein incorporated y reference in their entirety. In addition, humanized anti-IL-5
antibodies are described in various references and include relizumab (SCH55700) and
mepolizumab (SB240563) (
Greenfeder, et al., Respiratory Research, 2(2):71-79 (2001)). Mepolizumab (SB-240563) is a fully humanized monoclonal antibody (IgG
1, kappa, mAb) which is specific for human interleukin-5 (IL-5).
[0010] "Altered antibody" refers to a protein encoded by an altered immunoglobulin coding
region, which may be obtained by expression in a selected host cell. Such altered
antibodies are engineered antibodies (e.g., chimeric or humanized antibodies) or antibody
fragments lacking all or part of an immunoglobulin constant region, e.g., Fv, Fab,
or F(ab)
2 and the like.
[0011] "Altered immunoglobulin coding region" refers to a nucleic acid sequence encoding
altered antibody of the invention. When the altered antibody is a CDR-grafted or humanized
antibody, the sequences that encode the complementarity determining regions (CDRs)
from a non-human immunoglobulin are inserted into a first immunoglobulin partner comprising
human variable framework sequences. Optionally, the first immunoglobulin partner is
operatively linked to a second immunoglobulin partner.
[0012] "First immunoglobulin partner" refers to a nucleic acid sequence encoding a human
framework or human immunoglobulin variable region in which the native (or naturally-occurring)
CDR-encoding regions are replaced by the CDR-encoding regions of a donor antibody.
The human variable region can be an immunoglobulin heavy chain, a light chain (or
both chains), an analog or functional fragments thereof. Such CDR regions, located
within the variable region of antibodies (immunoglobulins) can be determined by known
methods in the art. For example
Kabat et al. (Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department
of Health and Human Services, National Institutes of Health (1987)) disclose rules for locating CDRs. In addition, computer programs are known which
are useful for identifying CDR regions/structures.
[0013] "Neutralizing" refers to an antibody that inhibits IL-5 activity by preventing the
binding of human IL-5 to its specific receptor or by inhibiting the signalling of
IL-5 through its receptor, should binding occur. A mAb is neutralizing if it is 90%
effective, preferably 95% effective and most preferably 100% effective in inhibiting
IL-5 activity as measured in the B13 cell bioassay (IL-5 Neutralization assay, see
Example 2C).
[0014] The term "high affinity" refers to an antibody having a binding affinity characterized
by a K
d equal to or less than 3.5 x 10
-11 M for human IL-5 as determined by optical biosensor anaylsis.
[0015] By "binding specificity for human IL-5" is meant a high affinity for human, not murine,
IL-5.
[0016] "Second immunoglobulin partner" refers to another nucleotide sequence encoding a
protein or peptide to which the first immunoglobulin partner is fused in frame or
by means of an optional conventional linker sequence (i.e., operatively linked). Preferably
it is an immunoglobulin gene. The second immunoglobulin partner may include a nucleic
acid sequence encoding the entire constant region for the same (i.e., homologous -
the first and second altered antibodies are derived from the same source) or an additional
(i.e., heterologous) antibody of interest. It may be an immunoglobulin heavy chain
or light chain (or both chains as part of a single polypeptide). The second immunoglobulin
partner is not limited to a particular immunoglobulin class or isotype. In addition,
the second immunoglobulin partner may comprise part of an immunoglobulin constant
region, such as found in a Fab, or F(ab)
2 (i.e., a discrete part of an appropriate human constant region or framework region).
Such second immunoglobulin partner may also comprise a sequence encoding an integral
membrane protein exposed on the outer surface of a host cell, e.g., as part of a phage
display library, or a sequence encoding a protein for analytical or diagnostic detection,
e.g., horseradish peroxidase, β-galactosidase, etc.
[0018] As used herein, an "engineered antibody" describes a type of altered antibody, i.e.,
a full-length synthetic antibody (e.g., a chimeric or humanized antibody as opposed
to an antibody fragment) in which a portion of the light and/or heavy chain variable
domains of a selected acceptor antibody are replaced by analogous parts from one or
more donor antibodies which have specificity for the selected epitope. For example,
such molecules may include antibodies characterized by a humanized heavy chain associated
with an unmodified light chain (or chimeric light chain), or vice versa. Engineered
antibodies may also be characterized by alteration of the nucleic acid sequences encoding
the acceptor antibody light and/or heavy variable domain framework regions in order
to retain donor antibody binding specificity. These antibodies can comprise replacement
of one or more CDRs (preferably all) from the acceptor antibody with CDRs from a donor
antibody described herein.
[0019] A "chimeric antibody" refers to a type of engineered antibody which contains naturally-occurring
variable region (light chain and heavy chains) derived from a donor antibody in association
with light and heavy chain constant regions derived from an acceptor antibody.
[0021] The term "donor antibody" refers to an antibody (monoclonal, or recombinant) which
contributes the nucleic acid sequences of its variable regions, CDRs, or other functional
fragments or analogs thereof to a first immunoglobulin partner, so as to provide the
altered immunoglobulin coding region and resulting expressed altered antibody with
the antigenic specificity and neutralizing activity characteristic of the donor antibody.
One donor antibody suitable for use in this invention is a non-human neutralizing
monoclonal antibody (i.e., murine) designated as 2B6, which was deposited with the
American Type Culture Collection (ATCC), Rockville, MD, USA, under accession number
HB 11783. The antibody 2B6 is defined as a high affinity, human-IL-5 specific (i.e.,
does not recognize murine IL-5), neutralizing antibody of isotype IgG
1 having the variable light chain DNA and amino acid sequences of SEQ ID NOs: 2 and
16, respectively, and the variable heavy chain DNA and amino acid sequences of SEQ
ID NOs: 1 and 15, respectively, on a suitable murine IgG constant region.
[0022] The term "acceptor antibody" refers to an antibody (monoclonal, or recombinant) heterologous
to the donor antibody, which contributes all (or any portion, but preferably all)
of the nucleic acid sequences encoding its heavy and/or light chain framework regions
and/or its heavy and/or light chain constant regions to the first immunoglobulin partner.
Preferably a human antibody is the acceptor antibody.
[0024] CDRs provide the majority of contact residues for the binding of the antibody to
the antigen or epitope. CDRs of interest in this invention are derived from donor
antibody variable heavy and light chain sequences, and include analogs of the naturally
occurring CDRs, which analogs also share or retain the same antigen binding specificity
and/or neutralizing ability as the donor antibody from which they were derived.
[0025] By 'sharing the antigen binding specificity or neutralizing ability' is meant, for
example, that although mAb 2B6 (see
U.S. Patent Nos. 5,683,892,
5,693,323,
5,783,184,
5,851,525, and
6,129,913) may be characterized by a certain level of antigen affinity, a CDR encoded by a
nucleic acid sequence of 2B6 in an appropriate structural environment may have a lower,
or higher affinity. It is expected that CDRs of 2B6 in such environments will nevertheless
recognize the same epitope(s) as 2B6. Exemplary heavy chain CDRs of 2B6 include SEQ
ID NO: 7; SEQ ID NO: 8; SEQ ID NO: 9; and exemplary light chain CDRs of 2B6 include
SEQ ID NO: 10; SEQ ID NO: 11; and SEQ ID NO: 12.
[0026] A "functional fragment" is a partial heavy or light chain variable sequence (e.g.,
minor deletions at the amino or carboxy terminus of the immunoglobulin variable region)
which retains the same antigen binding specificity and/or neutralizing ability as
the antibody from which the fragment was derived.
[0027] An "analog" is an amino acid sequence modified by at least one amino acid, wherein
said modification can be chemical or a substitution or a rearrangement of a few amino
acids (i.e., no more than 10), which modification permits the amino acid sequence
to retain the biological characteristics, e.g., antigen specificity and high affinity,
of the unmodified sequence. For example, (silent) mutations can be constructed, via
substitutions, when certain endonuclease restriction sites are created within or surrounding
CDR-encoding regions.
[0028] Analogs may also arise as allelic variations. An "allelic variation or modification"
is an alteration in the nucleic acid sequence encoding the amino acid or peptide sequences
of the invention. Such variations or modifications may be due to degeneracy in the
genetic code or may be deliberately engineered to provide desired characteristics.
These variations or modifications may or may not result in alterations in any encoded
amino acid sequence.
[0029] The term "effector agents" refers to non-protein carrier molecules to which the altered
antibodies, and/or natural or synthetic light or heavy chains of the donor antibody
or other fragments of the donor antibody may be associated by conventional means.
Such non-protein carriers can include conventional carriers used in the diagnostic
field, e.g., polystyrene or other plastic beads, polysaccharides, e.g., as used in
the BIAcore [Pharmacia] system, or other non-protein substances useful in the medical
field and safe for administration to humans and animals. Other effector agents may
include a macrocycle, for chelating a heavy metal atom, or radioisotopes. Such effector
agents may also be useful to increase the half-life of the altered antibodies, e.g.,
polyethylene glycol.
[0030] "Polypeptide" refers to any peptide or protein comprising two or more amino acids
joined to each other by peptide bonds or modified peptide bonds,
i.e., peptide isosteres. "Polypeptide" refers to both short chains, commonly referred to
as peptides, oligopeptides or oligomers, and to longer chains, generally referred
to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded
amino acids. "Polypeptides" include amino acid sequences modified either by natural
processes, such as posttranslational processing, or by chemical modification techniques
that are well known in the art. Such modifications are well described in basic texts
and in more detailed monographs, as well as in a voluminous research literature. Modifications
can occur anywhere in a polypeptide, including the peptide backbone, the amino acid
side-chains and the amino or carboxyl termini. It will be appreciated that the same
type of modification may be present in the same or varying degrees at several sites
in a given polypeptide. Also, a given polypeptide may contain many types of modifications.
Polypeptides may be branched as a result of ubiquitination, and they may be cyclic,
with or without branching. Cyclic, branched and branched cyclic polypeptides may result
from posttranslation natural processes or may be made by synthetic methods. Modifications
include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of
flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide
or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent
attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation,
demethylation, formation of covalent cross-links, formation of cysteine, formation
of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation,
hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing,
phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA
mediated addition of amino acids to proteins such as arginylation, and ubiquitination.
See, for instance,
PROTEINS - STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman
and Company, New York, 1993 and
Wold, F., Posttranslational Protein Modifications: Perspectives and Prospects, pgs.
1-12 in POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic
Press, New York, 1983;
Seifter, et al., "Analysis for protein modifications and nonprotein cofactors", Meth.
Enzymol. (1990) 182:626-646 and
Rattan, et al., "Protein Synthesis: Posttranslational Modifications and Aging", Ann
NY Acad Sci (1992) 663:48-62.
[0031] "Variant" as the term is used herein, is a polynucleotide or polypeptide that differs
from a reference polynucleotide or polypeptide respectively, but retains essential
properties. A typical variant of a polynucleotide differs in nucleotide sequence from
another, reference polynucleotide. Changes in the nucleotide sequence of the variant
may or may not alter the amino acid sequence of a polypeptide encoded by the reference
polynucleotide. Nucleotide changes may result in amino acid substitutions, additions,
deletions, fusions and truncations in the polypeptide encoded by the reference sequence,
as discussed below. A typical variant of a polypeptide differs in amino acid sequence
from another, reference polypeptide. Generally, differences are limited so that the
sequences of the reference polypeptide and the variant are closely similar overall
and, in many regions, identical. A variant and reference polypeptide may differ in
amino acid sequence by one or more substitutions, additions, deletions in any combination.
A substituted or inserted amino acid residue may or may not be one encoded by the
genetic code. A variant of a polynucleotide or polypeptide may be a naturally occurring
such as an allelic variant, or it may be a variant that is not known to occur naturally.
Non-naturally occurring variants of polynucleotides and polypeptides may be made by
mutagenesis techniques or by direct synthesis.
[0032] As used herein, "reduce" or "reducing" eosinophils refers to a decrease in the amount
of eosinophils observed in the blood of a patient after administration at least one
anti-IL-5 antibody.
[0033] As used herein "co-administration" or "co-administering" as used herein refers to
administration of two or more compounds to the same patient. Co-administration of
such compounds may be simultaneous or at about the same time (e.g., within the same
hour) or it may be within several hours, days, week, or months of one another, depending
on the dosing schedule of each compound. For example, a first compound may be administered
once weekly while a second compound is co-administered daily. By way of another example,
compounds may be co-administered if one compound is administered daily and the other
compound is administered once every three months.
[0034] As used herein "maximum plasma concentration" or "Cmax" means the highest observed
concentration of a substance (for example, at least one anti-IL-5 antibody) in mammalian
plasma after administration of the substance to the mammal.
[0035] As used herein "Area Under the Curve" or "AUC" is the area under the curve in a plot
of the concentration of a substance in plasma against time. AUC can be a measure of
the integral of the instantaneous concentrations during a time interval and has the
units mass*time/volume. AUC is typically calculated by the trapezoidal method (e.g.,
linear, linear-log). AUC is usually given for the time interval zero to infinity,
and other time intervals are indicated (for example AUC (t1,t2) where t1 and t2 are
the starting and finishing times for the interval). Thus, as used herein "AUC
0-24" refers to an AUC over a 24 hour period and AUC(0-inf) refers to AUC from over a
infinite time period..
[0036] As used herein "Tmax" refers to the observed time for reaching the maximum concentration
of a substance in plasma of a mammal after administration of that substance to the
mammal.
[0037] As used herein "serum or plasma half life" refers to the time required for half the
quantity of a substance administered to a mammal to be metabolized or eliminated from
the serum or plasma of the mammal by normal biological processes.
[0038] As used herein "disorder associated with excess eosinophil production" means any
disorder or disease in which atypical symptoms may manifest due to the production
of eosinophils. Disorders associated with excess eosinophil production include but
are not limited to, atopic asthma, atopic dermatitis, allergic rhinitis, non-allergic
rhinitis, asthma, severe asthma, chronic eosinophilic pneumonia, allergic bronchopulmonary
aspergillosis, coeliac disease, Churg-Strauss syndrome (periarteritis nodosa plus
atopy), eosinophilic myalgia syndrome, hypereosinophilic syndrome, oedematous reactions
including episodic angiodema, helminth infections, where eosinophils may have a protective
role, onchocercal dermatitis and Eosinophil-Associated Gastrointestinal Disorders,
including but not limited to, eosinophilic oesophagitis, eosinophilic gastritis, eosinophilic
gastroenteritis, eosinophilic enteritis and eosinophilic colitis, nasal micropolyposis
and polyposis, aspirin intolerance, asthma and obstructive sleep apnoe. Eosinophil-derived
secretory products have also been associated with the promotion of angiogenesis and
connective tissue formation in tumours and the fibrotic responses seen in conditions
such as chronic asthma, Crohn's disease, scleroderma and endomyocardial fibrosis (
Munitz A, Levi-Schaffer F. Allergy 2004; 59: 268-75,
Adamko et al. Allergy 2005; 60: 13-22,
Oldhoff, et al. Allergy 2005; 60: 693-6).
[0039] The therapeutic response induced by the methods of this invention is produced by
the binding on an anti-IL-5 antibody to human IL-5 and thus subsequently blocking
eosinophil stimulation. Thus, the methods of the present invention are highly desirable
for those persons experiencing an allergic and/or atopic response, or a response associated
with eosinophilia.
[0040] In one embodiment of the present invention, methods are provided for reducing eosinophils
in a human in need thereof, which method comprises administering to said human a composition
comprising at least one anti-IL-5 antibody, wherein at least one anti-IL-5 antibody
provides a mean maximum plasma concentration of said anti-IL-5 antibody of at least
about 1.03 ± 0.21 µg/mL and an Area Under the Curve value of said anti-IL-5 antibody
is at least about 15.5 ± 2.7 µg/day/mL.The maximum plasma concentration may be in
the range of about 12.1 ± 2.4 µg/mL to about 278 ±29 µg/mL. The AUC may be in the
range of about 207 ±34 µg/day/mL to about 4361 ± 168 µg/day/mL. Furthermore said at
least one anti-IL-5 antibody has serum half-life of about 16.2 ± 2.1 days to about
21.7 ± 2.8 days.
[0041] In another aspect, at least one anti-IL-5 antibody is to human IL-5. In another aspect,
at least one anti-IL antibody is neutralizing. The anti-IL-5 antibody of the present
invention may be humanized, fully human, murine or a fragment of any anti-IL-antibody
thereof. In another aspect, at least one anti-IL-5 antibody comprises a heavy chain
of SEQ ID NO: 19 and at least one anti-IL-5 antibody comprises a light chain having
SEQ ID NO: 21.
[0042] In another aspect of the present invention, the human is suffering from a disorder
associated with excess eosinophil production selected from the group consisting of
atopic asthma, atopic dermatitis, allergic rhinitis, non-allergic rhinitis, asthma,
severe asthma, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis,
coeliac disease, Churg-Strauss syndrome, eosinophilic myalgia syndrome, hypereosinophilic
syndrome, oedematous reactions including episodic angiodema, helminth infections,
onchocercal dermatitis eosinophilic oesophagitis, eosinophilic gastritis, eosinophilic
gastroenteritis, eosinophilic enteritis, eosinophilic colitis, nasal micropolyposis,
nasal polyposis, aspirin intolerance asthma, obstructive sleep apnoe, chronic asthma,
Crohn's disease, scleroderma and endomyocardial fibrosis.
[0043] In another aspect of the present invention the composition comprising at least one
anti-IL-5 antibody is administered subcutaneously, which may be at a dose of 250 mg.
A subcutaneous dose may be administered one to three times or more to a human. Mean
plasma concentration of said at least one anti-IL-5 antibody from a subcuntaneous
injection may be about 34.1 ± 12.1 µg/mL to about 38.2 ± 9.1 µg/mL. AUC of said at
least one anti-IL-5 antibody from a subcutaneous injection may be about 1110 ± 372
µg/day/mL to about 1196 ± 254 µg/day/mL.
[0044] In another aspect of the present invention, methods are provided wherein said composition
comprising an anti-IL-5 antibody is administered intramuscularly. Intramuscular injection
of a composition comprising at least one anti-IL-5 antibody may be administered at
a dose of 250 mg. The mean plasma concentration of said at least one anti-IL-5 antibody
from intramuscular injection may be about 46.9 ± 10.6 µg/mL and the AUC of said at
least one anti-IL-5 antibody may be about 1395 ± 348 µg/day/mL.
[0045] In yet another aspect of the present invention, methods are provided wherein said
composition comprising said at least one anti-IL-5 antibody is administered intravenously.
An anti-IL-5 antibody administered intravenously may be administered at a dose of
250 mg to a dose of 750 mg, which may be administered over the course of 20-60 minutes
or over about 30 minutes. The mean plasma concentration of said at least one anti-IL-5
antibody administered intravenously may be about 109 ± 17.0 µg/mL and the AUC of said
at least one anti-IL-5 antibody may be about 1557 ± 250 µg/day/mL.
[0046] The present invention also provides methods for reducing eosinophils in a human in
need thereof, comprising administering a composition comprising a first anti-IL-5
antibody and a second anti-IL-5 antibody. Methods are also provided herein wherein
at least one anti-IL-5 antibody is co-administered with a steroid.
[0047] Also, provided herein are methods of treating nasal polyposis, in a human, comprising
the step of administering to said human in need thereof an effective amount of a composition
comprising at least one anti-IL-5 antibody wherein said antibody comprises a heavy
chain and a light chain. In some aspects, the antibody comprises a heavy chain comprising
SEQ ID NO: 19 and/or the antibody comprises a light chain comprising SEQ ID NO: 21.
In another aspect, the nasal polyposis is severe.
[0048] In one embodiment, the size of at least one nasal polyp in said human is reduced
after at least one dose of said composition comprising at least one anti-IL-5 antibody.
The size of said at least one nasal polyp remains reduced for at least two months.
Administration of said composition comprising at least one anti-IL-5 antibody can
reduce or eliminates the need of said human for surgery for nasal polyposis.
[0049] In another aspect, the human with nasal polyps is also suffering from a disorder
associated with excess eosinophil production selected from the group consisting of
atopic asthma, atopic dermatitis, allergic rhinitis, non-allergic rhinitis, asthma,
severe asthma, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis,
coeliac disease, Churg-Strauss syndrome, eosinophilic myalgia syndrome, hypereosinophilic
syndrome, oedematous reactions including episodic angiodema, helminth infections,
onchocercal dermatitis eosinophilic oesophagitis, eosinophilic gastritis, eosinophilic
gastroenteritis, eosinophilic enteritis, eosinophilic colitis, nasal micropolyposis,
aspirin intolerance asthma, obstructive sleep apnoe, chronic asthma, Crohn's disease,
scleroderma and endomyocardial fibrosis. The composition comprising at least one anti-IL-5
antibody comprises a first anti-IL-5 antibody and a second anti-IL-5 antibody. The
composition comprising at least one anti-IL-5 antibody can be co-administered with
a steroid. The at least one anti-IL-5 antibody may be administered intravenously as
750 mg over about 30 minutes.
[0050] A skilled artisan will understand the various methods for measuring and calculating
the pharmacokinetic (for example, but not limited to, Cmax, AUC, Tmax, serum half-life)
and pharmacodynamic (for example, but not limited to, eosinophil levels) parameters
described herein. Furthermore, the skilled artisan will understand the various methods
for making statistical comparisons (for example, but not limited to, comparisons of
change from baseline to post-treatment and/or comparisons among treatment groups)
and/or analysis of the pharmacokinetic and pharmacodynamic parameters described herein.
[0051] The invention may be described in accordance with the numbered sentences below:
- 1. A method for reducing eosinophils in a human in need thereof, which method comprises
administering to said human a composition comprising at least one anti-IL-5 antibody,
wherein said anti-IL-5 antibody provides a mean maximum plasma concentration of said
anti-IL-5 antibody of at least about 1.03 ± 0.21 µg/mL and an Area Under the Curve
value of said anti-IL-5 antibody is at least about 15.5 ± 2.7 µg/day/mL.
- 2. The method of sentence 1, wherein said mean maximum plasma concentration is in
the range of about 12.1 ± 2.4 µg/mL to about 278 ±29 µg/mL.
- 3. The method of claim 1, wherein said AUC is in the range of about 207 ±34 µg/day/mL
to about 4361 ± 168 µg/day/mL.
- 4. The method of sentence 1, wherein said at least one anti-IL-5 antibody is to human
IL-5.
- 5. The method of sentence 4, wherein said at least one anti-IL antibody is neutralizing.
- 6. The method of sentence 1, wherein said at least one anti-IL-5 antibody is humanized.
- 7. The method of sentence 1, wherein said at least one anti-IL-5 antibody comprises
a heavy chain comprising SEQ ID NO: 19.
- 8. The method of sentence 1 wherein said at least one anti-IL-5 antibody comprises
a light chain comprising SEQ ID NO: 21.
- 9. The method of sentence 1, wherein said at least one anti-IL-5 antibody comprises
a heavy chain comprising SEQ ID NO: 19 and a light chain comprising SEQ ID NO: 21.
- 10. The method of sentence 1 wherein the human is suffering from a disorder associated
with excess eosinophil production selected from the group consisting of atopic asthma,
atopic dermatitis, allergic rhinitis, non-allergic rhinitis, asthma, severe asthma,
chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, coeliac disease,
Churg-Strauss syndrome, eosinophilic myalgia syndrome, hypereosinophilic syndrome,
oedematous reactions including episodic angiodema, helminth infections, onchocercal
dermatitis eosinophilic oesophagitis, eosinophilic gastritis, eosinophilic gastroenteritis,
eosinophilic enteritis, eosinophilic colitis, nasal micropolyposis, nasal polyposis,
aspirin intolerance asthma, obstructive sleep apnoe, chronic asthma, Crohn's disease,
scleroderma and endomyocardial fibrosis.
- 11. The method of sentence 1, wherein said composition comprising at least one anti-IL-5
antibody is administered subcutaneously.
- 12. The method of sentence 11, wherein said composition comprising at least one anti-IL-5
antibody is administered at a dose of 250 mg.
- 13. The method of sentence 11, wherein said subcutaneous dose is administered one
to three times.
- 14. The method of sentence 13, wherein the mean plasma concentration of said at least
one anti-IL-5 antibody is about 34.1 ± 12.1 µg/mL to about 38.2 ± 9.1 µg/mL.
- 15. The method of sentence 13, wherein the AUC of said at least one anti-IL-5 antibody
is about 1110 ± 372 µg/day/mL to about 1196 ± 254 µg/day/mL.
- 16. The method of sentence 1, wherein said composition comprising an anti-IL-5 antibody
is administered intramuscularly.
- 17. The method of sentence 16, wherein said composition comprising at least one anti-IL-5
antibody is administered at a dose of 250 mg.
- 18. The method of sentence 17, wherein said the mean plasma concentration of said
at least one anti-IL-5 antibody is about 46.9 ± 10.6 µg/mL and the AUC of said at
least one anti-IL-5 antibody is about 1395 ± 348 µg/day/mL.
- 19. The method of sentence 1, wherein said composition comprising an anti-IL-5 antibody
is administered intravenously.
- 20. The method of sentence 19, wherein said composition comprising at least one anti-IL-5
antibody is administered at a dose of 250 mg.
- 21. The method of sentence 19, wherein said composition comprising at least one anti-IL-5
antibody is administered at a dose of 750 mg.
- 22. The method of sentence 19, wherein said at least one anti-IL-5 antibody is administered
over about a 30 minute infusion.
- 23. The method of sentence 19, wherein said the mean plasma concentration of said
at least one anti-IL-5 antibody is about 109 ± 17.0 µg/mL and the AUC of said at least
one anti-IL-5 antibody is about 1557 ± 250 µg/day/mL.
- 24. The method of sentence 1, wherein said at least one anti-IL-5 antibody has serum
half-life of about 16.2 ± 2.1 days to about 21.7 ± 2.8 days.
- 25. The method of sentence 1, wherein said composition comprising at least one anti-IL-5
antibody comprises a first anti-IL-5 antibody and a second anti-IL-5 antibody.
- 26. The method of sentence 1, wherein said composition comprising at least one anti-IL-5
antibody is co-administered with a steroid.
Examples
[0052] The following examples illustrate various aspects of this invention. These examples
do not limit the scope of this invention which is defined by the appended claims.
Example 1 - Pharmacokinetics of an anti-IL-5 antibody in Healthy Volunteers
[0053] Pharmacokinetics in normal volunteers was evaluated following subcutaneous (sc),
intramuscular (im), and intravenous (iv) administration. The objectives of this study
were to estimate the bioavailability of a single 250 mg dose of mepolizumab (a humanized,
anti-IL-5 antibody described herein) from three different sc sites and an im site
compared with an iv dose and to make a preliminary assessment of the safety and tolerability
of mepolizumab and its effect on eosinophil counts in healthy volunteers. This was
an open, single dose, parallel group study. Human subjects were allocated to receive
doses of mepolizumab as shown in Table 1.
Table 1 Dose Allocation
No. of Subjects |
Dose |
Route |
Site of Injection |
12 |
250 mg |
Sc |
Abdomen - lower anterior wall |
12 |
250 mg |
Sc |
Arm - upper outer aspect |
12 |
250 mg |
Sc |
Thigh - upper outer aspect |
12 |
250 mg |
Im |
Lateral thigh |
12 |
250 mg |
IV |
Forearm vein |
[0054] Each human subject received one dose of study medication (mepolizumab) and was followed
for 12 weeks with blood samples taken at intervals for assay of mepolizumab and eosinophil
count.
[0055] Sixty healthy subjects, between 18 and 55 years of age, 23 males and 37 females were
recruited to achieve 12 evaluable subjects per group. At least four of one sex were
recruited to each dose group. Each 250 mg sc dose was administered as 2 x 125 mg (2
x 1ml) injections of mepolizumab, the im dose was administered as 1 x 250 mg (1 x
2ml) injection, and the iv dose was administered as an infusion over approximately
30 minutes.
[0056] Serial blood samples were collected pre-dose and nominally up to 12 weeks after administration
of mepolizumab. Plasma samples were assayed for mepolizumab using an immunoassay method
(Lower Limit of Quantitation [LLQ] 0.05 µg/mL for a 0.1 mL aliquot of 10% human plasma).
Non-compartmental pharmacokinetic analysis was used to derive the parameters AUC(0-inf),
Cmax, Tmax, and T1/2 for mepolizumab.
[0057] Following the 30 minute iv infusion, mepolizumab plasma concentrations declined in
a seemingly bi-exponential manner. Tmax ranged from 0.5 to 4 hours, relative to the
start of the 30 minute infusion.
[0058] Following administration of bolus sc injections at three different sites and the
bolus im injection, the mean mepolizumab plasma concentration-time profiles were similar
in shape. However, overall the mean plasma concentrations were higher following im
administration. Mepolizumab was absorbed slowly, with Tmax values ranging between
2 and 14 days. Table 2 summarizes the PK parameters for mepolizumab.
Table 2 Mean (SD) Pharmacokinetic Parameters for Mepolizumab Following Administration
at 3 Subcutaneous Sites, 1 Intramuscular Site, and Intravenous Administration of 250
mg
|
SC |
|
|
|
Abdomen (n = 12) |
Arm (n = 12) |
Thigh (n = 12) |
IM (n = 12) |
IV (n = 12) |
AUC0_inf, µg/day/mL |
1110 ± 372 |
1238 ± 228 |
1196 ± 254 |
1395 ± 348 |
1557 ± 250 |
CmaX, µg/mL |
|
34.9 ± 7.3 |
38.2 ± 9.1 |
46.9 ± 10.6 |
109 ± 17.0 |
Tmax, daysa |
34.1 ± 12.1 |
5 (3-14) |
5 (2-7) |
4 (3-7) |
0.08 (0.02-0.2) |
T½, days |
7 (4-14) |
20.4 ± 2.6 |
18.5 ± 3.5 |
19.2 ± 4.2 |
18.5 ± 2.3 |
|
17.9 ± 3.3 |
|
|
|
|
a Median (range).
AUC0-inf = area under plasma concentration-time curve from 0 to infinity; Cmax = maximum plasma concentration; IM = intramuscular; IV = intravenous; SC = subcutaneous;
Tmax = time to Cmax; T½ = terminal half life. |
Example 2 - Patients with Mild to Moderate Atopic Asthma
[0059] A multicentre, double-blind, randomized, placebo-controlled study was conducted in
men, 18-46 years of age, with mild atopic asthma (forced expiratory volume in 1 second
[FEV
1] ≥70% predicted and on β
2-agonists). The starting dose used in this study (0.05 mg/kg) was the lowest dose
administered to cynomolgus monkeys (0.05, 0.5, 5 or 50 mg/kg IV; n = 2/sex/group)
in a two-dose toxicity study; the other doses were based on the lowest dose in the
same toxicity study at which a >85% decrease in basal eosinophil counts was observed
(i.e. 5 mg/kg). Pharmacokinetic parameters were assessed after a single, 30-minute
IV infusion of mepolizumab 0.05 mg/kg (n = 4), 0.5 mg/kg (n = 5), 2.5 mg/kg (n = 8)
or 10 mg/kg (n = 8) (Table 3). Plasma mepolizumab concentrations declined bi-exponentially
after the infusion, C
max (mean ± SD) ranged from 1.03 ± 0.21 µg/mL at the 0.05 mg/kg dose level to 215 ± 28
µg/mL at the 10 mg/kg dose level and T
max occurred at 0.5-3 hours. Both plasma clearance and volume of distribution at steady
state were similar across the dose range, indicating linear pharmacokinetics. There
was little inter-subject variability in the area under the plasma concentration-time
curve (AUC) or C
max (coefficients of variation were generally <20%). The mean (± SD) terminal half-life
was relatively constant across doses, ranging from 19.0 ± 2.5 days with 10 mg/kg to
20.0 ± 1.9 days with 0.5 mg/kg, and mepolizumab was quantifiable in plasma for up
to 16 weeks post-dose in the majority of subjects. (Table 3) In terms of pharmacodynamics,
mepolizumab was associated with a persistent dose-dependent decrease in peripheral
eosinophils, which was apparent at all doses and was maintained until the final follow-up
visit at Week 16 in patients on the 10 mg/kg dose.
Table 3. Pharmacokinetic parameters (mean ± SD) for mepolizumab following a single
intravenous infusion in men with mild atopic asthma
|
Mepolizumab dose (mg/kg) |
|
0.05 (n = 4) |
0.5 (n = 5) |
2.5 (n = 8) |
10 (n = 8) |
AUC0-inf, µg/day/mL |
15.5 ± 2.7 |
168 ± 19 |
846 ± 164a |
3345 ± 324 |
Cmax, µg/mL |
1.03 ± 0.21 |
10.6 ± 2.2 |
51.4 ± 7.9a,b |
215 ± 28 |
T½,days |
19.7 ± 7.6 |
20.0 ± 1.9 |
19.3 ± 2.9 |
19.0 ± 2.5 |
Plasma clearance, mL/h/kg |
0.137±0.022 |
0.125±0.014 |
0.129 ± 0.023 |
0.126 ± 0.013 |
Steady state volume of distribution, mL/kg |
85.0 ± 19.8 |
82.2 ± 14.5 |
80.6 ± 7.8 |
78.9 ± 11.0 |
a Data from one human subject excluded, due to incorrect dosing.
b Cmax value for one subject excluded, as it was approximately 4-5-fold higher than other
values in the cohort.
AUC0-inf = area under plasma concentration-time curve from 0 to infinity; Cmax = maximum plasma concentration; T½ = terminal half life. |
[0060] Similar pharmacokinetics were reported in a further double-blind, randomized, placebo-controlled
study in men, 18-43 years of age, with mild asthma (FEV
1 >64% predicted and on β
2-agonists with or without inhaled corticosteroids at 400-1000 µg/day) who received
a single IV infusion of mepolizumab 0.5 mg/kg (n = 4), 2.5 mg/kg (n = 4) or 10 mg/kg
(n = 4). A persistent and dose-dependent reduction in peripheral eosinophil count
relative to baseline was observed in most patients treated with mepolizumab (estimated
maximal decrease of ~85%). The duration of eosinophil suppression increased with increasing
dose, the maximal reduction in eosinophil count occurring approximately 3-4 days after
C
max.
[0061] The pharmacokinetics of mepolizumab following multiple dosing were also evaluated
in patients with asthma as part of a multicentre, double-blind, randomized, placebo-controlled,
parallel-group study. Three IV infusions of mepolizumab 250 mg (n = 120) or 750 mg
(n = 116) or placebo (n = 126) were administered at intervals of 1 month to patients,
18-55 years of age, with persistent mild-to-moderate asthma (FEV
1 50-80% predicted, managed with inhaled beclomethasone dipropionate ≤1000 µg/day or
equivalent). Dose-proportional and time-independent pharmacokinetics were observed
with repeat dosing in this population. In addition, both mepolizumab doses reduced
blood eosinophils by approximately 80% from baseline (p < 0.001 vs placebo). This
decrease was apparent 1 week after the first infusion and was maintained for 12 weeks
after the last infusion (to Week 20). Induced sputum was examined in a subgroup of
37 patients. This showed that sputum eosinophil numbers also decreased with mepolizumab
250 mg and 750 mg, starting 4 weeks after the first infusion and persisting to the
final follow-up visit at Week 20; the reduction from baseline to Week 12 was statistically
significant for mepolizumab 750 mg (p = 0.013). Neither circulating nor sputum eosinophil
levels changed significantly in the placebo group. Interestingly, the profound decrease
in the number of eosinophils in the blood was not accompanied by a parallel reduction
in bronchial mucosa or bone marrow eosinophils: while the reduction in blood was approximately
80% from baseline, the reduction in bronchial mucosa was approximately 50% from baseline.
It is possible that airway eosinophils are less dependent upon IL-5, or that depletion
of eosinophils in the bronchial mucosa may require a longer period of treatment.
[0062] Time-independent pharmacokinetics were also observed in a double-blind, placebo-controlled,
parallel-group study after repeated SC administration of mepolizumab. Men and women,
aged 19-50 years, with mild asthma received three SC doses of mepolizumab 250 mg (n
= 8) or placebo (n = 8). The first two doses were given 6 weeks apart and the third
dose was given 2 weeks
[0063] Mepolizumab was quantifiable for up to 16 weeks post-dosing in the majority of human
subjects receiving a single iv dose. Two subjects had quantifiable concentrations
at time zero that were less than 1 % of the Cmax values observed in these subjects.
These quantifiable pre-dose concentrations were set to zero for the computation of
AUC(0-inf).
[0064] One other subject received a dose of approximately 0.0877 mg/kg instead of 2.5 mg/kg.
AUC, Cmax, and Tmax data from this subject were excluded and CL and Vss values for
this subject were calculated using the actual dose of 0.0877 mg/kg.
[0065] For the compartmental analysis, a two-compartment model appeared to fit the concentration-time
profiles reasonably well, with the exception of the 0.05 mg/kg dose in which the number
of data points was limited due to sparse sampling and non-quantifiable concentrations.
Goodness of fit was evidenced by the generally low standard errors (Percent Coefficient
of Variation [CV%]<35%). The AUC(0-inf), CL, and Vss data generated by the compartmental
analysis were also generally in close agreement with data from the non-compartmental
analysis. The majority of the area under the plasma concentration versus time curve
(generally >90%) was associated with the terminal phase. The initial and terminal
phase half-life values were approximately 2 and 20 days, respectively.
Example 3 - Comparison of Single IV infusion in human patients with Mild Asthma
[0066] Following administration of 0.5 to 10 mg/kg doses as a single 30 minute iv infusion
to males with mild asthma, mepolizumab exhibited dose-proportional PK and a long elimination
half-life of approximately 20 days (Table 4). Plasma clearance and steady-state volume
of distribution were relatively constant across the dose range studied (Table 4).
The inter-subject variability in PK parameters of mepolizumab was low (CV% values
of 20% or less).
Table 4 Mean (SD) Pharmacokinetic Parameters for Mepolizumab Following a Single Thirty-minute
Infusion of Mepolizumab to Males with Mild Asthma
|
Dose Range (mg/kg) |
Parameter |
0.5 mg/kg n=4 |
2.5 mg/kg n=4 |
10 mg/kg n=4 |
AUC(0-inf) (µg. day/mL) |
207 (34) |
1327 (247) |
4361 (168) |
Cmax (µg/mL) |
12.1 (2.4) |
79.0 (4.3) |
278 (29) |
CL (mL/h/kg) |
0.103 (0.017) |
0.081 (0.015) |
0.096 (0.004) |
Vss (mL/kg) |
68.4 (2.5) |
55.4 (5.2) |
59.3 (3.7) |
T1/2 (days) |
20.9 (4.0) |
21.7 (2.8) |
20.9 (2.6) |
Example 4 - Subcutaneous doses in Patients with Mild Asthma
[0067] Three sc doses of 250 mg were administered to patients with mild asthma using the
following regimen: the first and second doses were separated by six weeks with the
second and third doses separated by two weeks. The data indicate that mepolizumab
has a bioavailability of approximately 50% following sc injections into the lateral
abdominal wall as compared with iv infusion administered to another group of patients.
As expected, based on the short time separation between the three doses (6 and 2 weeks)
relative to the long terminal half-life of mepolizumab (20 days), the mean AUC and
Cmax were approximately 65% and 80%, respectively, higher after the third dose compared
with after the first dose. The drug was absorbed slowly with Tmax values ranging between
approximately 2 and 14 days. Mean PK parameters for mepolizumab are summarized in
Table 5.
Table 5 Mean (SD) Pharmacokinetic Parameters for Mepolizumab Following Single or Repeated
Subcutaneous Administration of 250 mg Mepolizumab
Parameter (units) |
Dose 1 (N=8) |
Dose 3 (N=8) |
AUC(0-inf) (µg.d/mL) |
560 (197) |
924 (189) |
Cmax (µg/mL) |
17.7 (7.1) |
32.2 (7.8) |
Tmax (days)1 |
4.50 (3.00-7.02) |
8.01 (2.02-13.96) |
T½ (days) |
20.5 (5.3) |
16.2 (2.1) |
1. Data presented as median (range). |
[0068] Individual concentration-time profiles following the first dose administration were
fitted to a one-compartment model with first order absorption. The mean parameter
values were used to simulate a concentration-time profile following administration
of the dosing regimen employed in this study. The predicted average concentrations
following the third dose fall within the range of observed concentrations, suggesting
time independent pharmacokinetics.
Example 5
[0069] Following three monthly administrations of either 250 mg or 750 mg iv infusions,
plasma concentrations of mepolizumab were generally quantifiable at all study visits.
Based on these preliminary data, mean plasma concentrations of mepolizumab at each
visit increased in an approximately dose-proportional manner between the 250 and 750
mg doses (Table 6). The means of the actual concentrations at each visit were similar
to the predicted multiple-dose concentration data which were simulated using a 2-compartment
iv infusion model and pharmacokinetic parameters estimated from previous single-dose
data (Table 6). Thus, mepolizumab exhibits dose-proportional and time-independent
pharmacokinetics.
Table 6 Mean (SD) Plasma Mepolizumab Concentrations (microgram/mL) by Dose and Visit
|
Visit 3 Post-Infusion |
Visit 4 |
Visit 5 |
Visit 6 Pre-dose |
Visit 8 Pre-dose |
Visit 8 Post-dose |
Visit 10 |
Visit 11 |
Visit 12 |
Days |
1 |
8±2 |
15±2 |
29±2 |
57±7 |
57±7 |
85±7 |
113±7 |
141±7 |
Dose (mg) |
n=55 |
n=53 |
n=51 |
n=51 |
n=86 |
n=49 |
n=36 |
n=32 |
n=25 |
250 |
90.0 (33.2) |
34.8 (15.4) |
23.1 (6.4) |
14.0 (11.5) |
18.9 (8.1) |
115 (40) |
22.2 (9.1) |
7.03 (3.79) |
3.17 (1.77) |
|
|
|
|
|
|
|
|
|
|
|
Visit 3 Post_ Infusion |
Visit 4 |
Visit 5 |
Visit 6 Pre-dose |
Visit 8 Pre-dose |
Visit 8 Post-dose |
Visit 10 |
Visit 11 |
Visit 12 |
Days |
1 |
8±2 |
15±2 |
29±2 |
57±7 |
57±7 |
85±7 |
113±7 |
141±7 |
Dose (mg) |
n=47 |
n=46 |
n=45 |
n=42 |
n=84 |
n=53 |
n=47 |
n=42 |
n=27 |
750 |
221 (60) |
90.9 (34.3) |
60.2 (15.5) |
34.5 (9.9) |
49.0 (14.1) |
254 (74) |
51.2 (19.5) |
18.2 (7.8) |
7.04 (3.39) |
Note: The number of days for visits 4 to 12 were days relative to the first dose of
mepolizumab. |
Example 5 - Human Patients with Hypereosiniphilic Syndrome
[0070] Following 9 monthly administrations (0 to 32 weeks) of 750 mg iv infusions, plasma
concentrations of mepolizumab were quantifiable at all study visits (from post-dose
Day 1) for all human patients who had blood samples drawn, except at one visit for
one patient. Based on preliminary data, the mean concentration values were similar
to those in the previous examples presented above following 750 mg of mepolizumab
by IV injection over aout 30 minutes (Table 7). The means of the actual concentrations
at each visit were similar to the predicted multiple-dose concentration data which
were simulated using a 2-compartment iv infusion model and pharmacokinetic parameters
estimated from previous single-dose data (Table 7). Thus, mepolizumab pharmacokinetics
in patients with HES are similar to those previously seen.
Table 7
Mean (SD) Mepolizumab Plasma Concentration by Week
Week (Day range)1,2 |
N |
Mean (SD) [µg/mL] |
CV% |
Week 0 (1 post-infusion) |
37 |
225 (74.7) |
33 |
Week 1 (6-10) |
38 |
85.0 (23.8) |
28 |
Week 2 (13-17) |
36 |
58.0 (17.7) |
31 |
Week 3 (19-24) |
35 |
41.5 (16.9) |
41 |
Week 4 (25-37) |
44 |
31.4 (13.7) |
44 |
Week 8 (54-65) |
38 |
43.6 (20.1) |
46 |
Week 16 (110-134) Pre-infusion |
36 |
44.5 (24.9) |
56 |
Week 16 (110-134) Post-infusion |
37 |
263 (91.3) |
35 |
Week 24 (164-196) |
32 |
57.6 (40.6) |
71 |
Week 32 (221-232) |
30 |
48.3 (30.8) |
64 |
Week 36 (239-266) |
29 |
53.7 (26.0) |
49 |
Post Week 36 (267-361) |
4 |
31.4 (22.3) |
71 |
1. The range of days relative to the first dose of mepolizumab.
2. The two quantifiable pre-dose values are not included. |
Example 6 - Pharmacokinetic/Pharmacodynamic Relationships
[0071] Following administration of 0.5 to 10 mg/kg iv mepolizumab, a persistent and dose-dependent
reduction in peripheral eosinophil count relative to baseline was observed in the
majority of patients who received mepolizumab. The duration of the suppression in
cell count increased with increasing dose. Maximal depression in cell count occurred
approximately 3 to 4 days after maximum plasma concentrations were achieved. The relationship
between % baseline eosinophil counts and plasma concentrations of mepolizumab was
well described using an indirect pharmacologic response model with inhibition of the
synthesis (production) rate constant. The estimated maximal decrease in eosinophil
count following administration of mepolizumab was approximately 85% from baseline
and the concentration of drug resulting in half-maximal effect on eosinophil count
(IC
50) was approximately 0.4 µg/mL.
Example 7 - Human Patients with Nasal Polyps
[0072] Rational: 90% of nasal polyps are characterised by prominent eosiophilia. IL-5 is key in eosinophilic
differentiation and survival and its antagonism is a potential novel treatment strategy
for patients with nasal polyps.
[0073] Methods: 30 subjects with severe nasal polyposis (grades 3-4) were randomized in double blind
fashion to receive either 2 single IV injections (28 days apart) of 750mg of mepolizumab,
a humanized anti-interleukin-5 monoclonal antibody (n=20), or placebo (n=10). Changes
in nasal polyp score and in comparative nasal polyp score were assessed relative to
baseline (week 0) at 1 and 2 months post last dose (week 8 and 12). A 1 point reduction
in these endoscopic assessments is considered clinically significant.
[0074] Results: No differences in baseline values were observed between mepolizumab and placebo.
A significant reduction was observed in nasal polyp score with Mepolizumab vs placebo
at week 8 (60% vs 10%, p=0.011) and week 12 (65% vs 20%, p=0.025). 65% subjects on
mepolizumab showed a 'much better' or 'better' improvement of comparative nasal polyp
score compared to 10% on placebo by week 8 and 70% on mepolizumab vs 20% on placebo
at week 12. Over 50% of subjects on mepolizumab demonstrated improvement on blinded
assessment of CT scans by three independent observers by week 8. The requirement for
surgery was also reduced in the group on mepolizumab with 15% subjects requesting
surgery in the group on mepolizumab vs 50% in the group on placebo by week 12. Individual
response and magnitude of response is maintained across the endpoints analysed.
1. An anti-IL-5 antibody for reducing eosinophils in a human suffering from a disorder
associated with excess eosinophil production selected from the group consisting of
atopic asthma, atopic dermatitis, allergic rhinitis, non-allergic rhinitis, asthma,
severe asthma, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis,
coeliac disease, Churg-Strauss syndrome, eosinophilic myalgia syndrome, hypereosinophilic
syndrome, oedematous reactions including episodic angiodema, helminth infections,
onchocercal dermatitis eosinophilic oesophagitis, eosinophilic gastritis, eosinophilic
gastroenteritis, eosinophilic enteritis, eosinophilic colitis, nasal micropolyposis,
nasal polyposis, aspirin intolerance asthma, obstructive sleep apnoe, chronic asthma,
Crohn's disease, scleroderma and endomyocardial fibrosis, wherein said anti-IL-5 antibody
is to be administered to said human in a composition which comprises said at least
one anti-IL-5 antibody, and provides a mean maximum plasma concentration of said anti-IL-5
antibody of at least 1.03 ± 0.21 µg/mL and an Area Under the Curve(0-inf) value of said anti-IL-5 antibody is at least 15.5 ± 2.7 µg×day/mL.
2. The anti-IL-5 antibody for the use according to claim 1, wherein said mean maximum
plasma concentration is in the range of 12.1 ± 2.4 µg/mL to 278 ±29 µg/mL or wherein
said AUC(0-inf) is in the range of 207 ±34 µg×day/mL to 4361 ± 168 µg×day/mL.
3. The anti-IL-5 antibody for the use according to claim 1, wherein said at least one
anti-IL-5 antibody is neutralizing and is to human IL-5.
4. The anti-IL-5 antibody for the use according to claim 1, wherein said at least one
anti-IL-5 antibody comprises a heavy chain comprising SEQ ID NO: 19 and/or comprises
a light chain comprising SEQ ID NO: 21.
5. The anti-IL-5 antibody for the use according to claim 1, wherein said composition
comprising at least one anti-IL-5 antibody is to be administered subcutaneously.
6. The anti-IL-5 antibody for the use according to claim 5, wherein said composition
comprising the antibody is to be administered at a dose of 250 mg.
7. The anti-IL-5 antibody for the use according to claim 5, wherein said subcutaneous
dose is to be administered one to three times.
8. The anti-IL-5 antibody for the use according to claim 5, wherein the mean plasma concentration
of said antibody is 34.1 ± 12.1 µg/mL to 38.2 ± 9.1 µg/mL or wherein the AUC(0-inf) of said antibody is 1110 ± 372 µg×day/mL to 1196 ± 254 µg×day/mL.
9. The anti-IL-5 antibody for the use according to claim 1, wherein said composition
comprising the antibody is to be administered intramuscularly.
10. The anti-IL-5 antibody for the use according to claim 9, wherein said composition
comprising the antibody is administered at a dose of 250 mg.
11. The anti-IL-5 antibody for the use according to claim 10, wherein said the mean plasma
concentration of said antibody is 46.9 ± 10.6 µg/mL and the AUC(0-inf) of said antibody is 1395 ± 348 µg×day/mL.
12. The anti-IL-5 antibody for the use according to claim 1, wherein said composition
comprising the antibody is to be administered intravenously.
13. The anti-IL-5 antibody for the use according to claim 12, wherein said the mean plasma
concentration of said antibody is 109 ± 17.0 µg/mL and the AUC(0-inf) of said antibody is 1557 ± 250 µg×day/mL.
14. The anti-IL-5 antibody for the use according to claim 1, wherein said antibody has
serum half-life of 16.2 ± 2.1 days to 21.7 ± 2.8 days.
15. The anti-IL-5 antibody for the use according to claim 1, wherein said composition
comprising at least one anti-IL-5 antibody is co-administered with a steroid.